Dendritic cells (DC) are innate immune effectors and are critically involved in regulating T-cell immunity. DC/Tcell interactions play a pivotal role in the inflammatory bone disorders like rheumatoid arthritis & periodontitis. Periodontitis results from the interplays between specific sub-gingival microorganisms (biofilms) and the host immune-inflammatory responses, a prime cause of tooth loss in adults. Patients with periodontitis may demonstrate increased risk for systemic disorders including coronary heart disease, bacterial pneumonia & preterm low birth weight baby, which threatens our general health, increases demands on our healthcare and imposes financial burdens. Our labs focus on the basic mechanisms of periodontitis with the long-term goal to identify new molecular targets and develop novel therapeutics for treating periodontitis. We have established informative experimental periodontitis model using "diabetic" NOD and "humanized" NOD/SCID mice to study the innate immunity & T-cell-mediated responses to an oral pathogen Actinobacillus actinomycetemcomitans (Aa) and also developed a novel in-vitro co-culture system to identify the basic disease mechanisms regarding CD11c+ dendritic cell (DC)-derived osteoclasts (OC)/T-cells interactions with Aa. Moreover, we showed that in enhanced alveolar bone loss in vivo is strongly correlated with: i) CD11c+DC carrying elevated co-stimulatory & Th1-inducing ability; ii) higher proliferation of Aa-specific Th-cells expressing receptor activator of NF-kB ligand (RANKL) and IFN-?/Th1 cytokines, which promote alveolar bone loss and tissue inflammation in vivo. Further, differential expression of "suppressor of cytokine signaling" (SOCS) affects DC-derived OC/T-cells interactions, subsequent inflammatory responses and bone resorption. To date, the ontogenesis and genetic regulations of innate immunity involved in the enhanced osteoclastogenesis and increased risk of developing periodontitis remains unclear. Here, we proposed to study the cellular and molecular interactions regarding how CD11c+DC directly contribute to the enhanced osteoclastogenesis in diabetic NOD mice via adoptive transfer in vivo and how the expression of SOCS1, 3 & 5 proteins differentially regulate the innate inflammatory response, alveolar bone loss and the development of Aa-specific RANKL(+)-Th1/Th2 cells via DC-derived OC/T-cell+Aa cultures and adenovector-mediated gene transfer of SOCS genes into CD11c+DC derived from diabetic & non-diabetic NOD vs. control diabetes-resistant NOR mice for comparisons/correlations. The new information obtained will enhance our understanding of the interactions for oral homeostasis and dissecting the underlying molecular mechanism for future in-vivo studies; in particular, linking the ontogenic features of innate immunity to oral pathogen with adaptive T-cell immunity and enhanced alveolar bone loss seen in diabetes, and, facilitate the exploration of novel strategies of targeting DC subset(s) and cytokine regulators (i.e., SOCS) as the potential therapeutics for regulating the innate immunity not only the inflammation but also subsequent bone destruction. [unreadable] [unreadable] [unreadable]